a b agenda 议程 risk management in the manufacture of ... · 6 risk ranking atrix and follow -up...
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叶渊明 多功能车间生产注册产品(中间体 / 原料药)的风险管理
Risk Management in the Manufacture of Different Regulated Products in Shared Workshops & Facilities多功能车间生产注册产品(中间体/原料药)的风险管理
Gary Ye叶渊明May 12, 2013
Agenda 议程
• Multi-purpose Workshop Risk Assessment 风险评估• Evolving Design Concept 设计理念变迁• MPW Management 多功能车间管理• Project Management 项目管理• People Management 人员管理• Summary 小结
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What is Risk? 什么是风险?
ICH Q9 Definition ICH Q9的定义
“Risk is defined as “the combination of the probability of occurrence of harm and severity of that harm.”风险的定义:”危害发生的可能性和严重性的组合”。
Risk Analysis Tools & Process Validation 3
保护的程度-外部的污染
层次II 层次III
层次I 层次II
层次I 层次I
关键程度
暴露程度
开放环境
密闭系统
产品受污染可能性-设备
专用设备,专用车间
多功能设备-多功能车间
污染来源:设备残留,管路残留,地面墙面残留,垫圈残留,包装桶残留,服装残留等。。。。
污染来源:灰尘,异物
Use Preliminary Hazard Analysis (PHA) in Assessing Risk at Dedicated Workshop & Multipurpose Workshop使用初步危害分析比较专用车间和多功能车间的风险
Frequency 频率 /Severity 严重性
Very Unlikely几乎不可能
Occasional 偶然的
Probable很可能的
Frequent频繁的
Catastrophic灾难性的
OOS/Contami-nation
Critical 关键的
Different Impurity profile
Major 主要的
Cleaning failure
Minor轻微的
Risk Analysis Tools6
Risk Ranking Matrix and Follow-up Actions风险排列矩阵和风险降低措施
Acceptable可接受的
Not Acceptable不可接受的
Not Acceptable不可接受的
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Typical Difficulties in Multi-purpose Workshop 多功能车间典型困难
• Changeover Cleaning 换产品清洗• Changeover Management 产品切换工作管理• Shared equipment and hoses 公用管路管线/设备• Production in Parallel 同时生产• People Management & Training 人员管理及培训
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1. Complaints 异物投诉2. Unexpected Impurities 异常杂质3. OOS/OOT4. GMP Audit Failure GMP 审计失败5. Mistakes Made by People 人员犯错
From Design Perspective 从设计视角来看
• Typical Old-fashion Design of Shared Workshop 传统车间设计
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Material Preparing Room
Weighting Room
Solid Material Temp-storage Liquid Material Temp-storage
Instrument RoomVacant
Spare Parts Room
Synthesize Area
Material Transfer
Material TransferMaterial Temp-storage
3F
Typical Old-fashion Design of Shared Workshop 传统车间设计
Material Transfer
Utility Room
Purify Water Room
Power RoomVacant Room
Fire Protection Room Centrifugal AreaCentrifugal Area
Vestibule
Office Room
Shoes Changing Room
Man's First Changing Room
Man's Second Changing Room
Woman's First Changing Room
Woman's Second Changing Room
Air Lock
Laundry Room
Tidy Room
Material Transfer
Drying Room
Anti-explosion Air Lock
Corridor
Cleaning Tool
Tool Cleaning
Container Storage
Container Cleaning
Waste Transfer Outer Packaging Room Inner-Packaging & Pending Room
Air Lock
Pulverizing Room
Inner Package Temp-Storage
Dust Collecter Unpack
Cleaning Tool
Tool Cleaning
Container Storage
Container Cleaning
Waste Transfer Outer Packaging Room Inner-Packaging & Pending Room
Air Lock
Pulverizing Room
Inner Package Temp-Storage
Dust Collecter Unpack
Anti-explosion Air Lock
Drying Room
Crystallize Room
Synthesize Area
Centrifugal Area
Intermediate Temp-storage Room
Crystallize Room
Drying Room Drying Room Drying Room
Drying Room Drying Room
Centrifugal AreaCentrifugal Area
Centrifugal Area Centrifugal Area
Cleaning Room
2F
1F
New Design Concept 全新设计理念
• Full HVAC System Supported Workshop 全空调系统配备的车间• Isolated Production Bay 分隔的生产区域• No Open Operation 无敞开操作• High Level of Using gravity 高度利用位差• Isolated Dispensing & Charging Area 单独配料及投料区• Solid Material Charging Devices 固体投料装置• Washing-Filtration-Drying Together 二合一/三合一设备的使用• CIP System Support CIP系统• TCU System TCU系统• Much Ideal Drying & packaging Area 更合理的烘房及包装区域
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Understanding of ICH Guidelines对ICH 指南的理解
• ICH Q8 Pharmaceutical Development 药品开发过程• ICH Q9 Quality Risk Management 质量风险管理• ICH Q10 Pharmaceutical Quality System 医药质量系统• ICH Q11 Development and Manufacturing of Drug Substance 开发和生产原
料药• QbD Concept 质量源于设计理念的贯穿
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ICH Q8/9/10 Adopted Separately分别采用
Q8 Q9 Q10
Enhanced Product and Process Understanding加强的产品和工艺理解
Challenge挑战:Acquisition and management of knowledge知识信息的获取和管理
Robust quality systems可靠的质量体系
Challenge挑战:What will our Quality System look like going forward?我们的质量体系以后会变成怎样?
Application of Quality Risk Management Principles/Tools质量风险管理原则/工具的应用
Challenge挑战:What do we assess against?我们评估的依据是什么?
12 Quality by Design (QbD)
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Combining Q8, Q9 & Q10 相结合
+ +
BENEFITS 优点
Quality by Design 质量源于设计
Lower Risk Operations低风险的操作
Innovation 创新
Continual Improvement 持续改进
13 Quality by Design (QbD)
Combining Q8, Q9 & Q10
Q8 Q9 Q10
+ +
REGULATORY FLEXIBILITY 法规的灵活性
Risk based regulatory decisions 基于风险的管理决策
Higher degree of self management of product/process changes产品/ 工艺变更高水平的自我管理
Reduction of inspections 减少法规审查
Real time assurance of quality 即时质量保证
14 Quality by Design (QbD)
Project Management 项目管理
• R&D and Pilot Production Stage 研发及试生产阶段• Process Validation Stage and Commercial Production
工艺验证阶段及商业化生产阶段
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Process project from
MarketProject Team
Develop method for IPC
& product release
Write analytical method transfer
report
Analytical chemists
Process developmentLab sample
qualification
Write process transfer report
Development report
Process chemists
Pilot production
plan
Draft of M。batch sheet
Notify the production
EHS Evaluation/Plant
Production finalizes the batch sheet
Acceptance from EHS,
Engineering/production
Acceptance from QC
Pilot production
starts
EHS/QA approvalCompletion
of production Process chemists
tech and QC support
Campaign report
QA review and release the batch
Process R&D – Project Management 研发阶段的项目管理
Project evaluationProject notification
Formulation Trail
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Process Validation & Change Control工艺验证及变更管理
Pilot Production
Pilot Production Review
Quality Risk Assessment
PV Protocol Preparation
Master Batch Sheet Preparation
Trail Batch Production
Validation Batch Production
Validation Report
Registration
Change Management
People Management 人员管理
• EHS Expertise & GMP Expertise EHS专业技能-Managerial Qualification Program 管理人员资格认定项目-Shared GMP/Quality Culture 对GMP文化的高度认同
• GMP & Technical Professionals GMP和技术人员-Operators Qualification Program 操作工资格认定
• Process Understanding 工艺理解-QRA, CPP & CQA
• Clear Role & Responsibilities 明晰的角色和职责-Equipment Management 设备管理-Material Management 物料管理-Housekeeping 定置管理-Documentations 文件记录
• Risk Based Tasks Management 基于风险的任务管理-HAZOP 工艺安全及可操作性风险评估-FMEA 失败模式及影响分析-Checklists 检查表
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Summary 小结
• 多功能车间是原料药生产企业质量风险最大的区域之一,需要建立系统的管理方案。感谢ICH指南,企业可以运用质量风险管理的理念和工具,从车间及产品设计入手改善生产区的格局,同时运用QRA提高对工艺的理解,强化车间的内部管理(尤其是产品切换,人员管理,清洁验证等),从根源上降低质量风险。Multi-purpose workshop is one of the highest quality risk area in API production, systematical management protocol should be in place to tackle this difficulties. Thanks to ICH guidelines, enterprises can take advantage of quality risk management concept and its tool, to optimize production setup starting from design phase. Meanwhile, QRA and high level understanding of processes are needed. Enterprises also need to improve the production management (especially product changeover, people management and cleaning management etc. ), to decrease quality risk dramatically from bottom level.
• 以上经验和观点的分享,仅代表个人观点,欢迎同行批评指正及探讨。Personal perspective only, critics and feedbacks are highly appreciated.
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Questions?疑问?
Thanks!感谢!
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